EP0008877B1 - Dérivés d'acide clavulanique, un procédé pour leur préparation et leurs compositions - Google Patents

Dérivés d'acide clavulanique, un procédé pour leur préparation et leurs compositions Download PDF

Info

Publication number
EP0008877B1
EP0008877B1 EP79301557A EP79301557A EP0008877B1 EP 0008877 B1 EP0008877 B1 EP 0008877B1 EP 79301557 A EP79301557 A EP 79301557A EP 79301557 A EP79301557 A EP 79301557A EP 0008877 B1 EP0008877 B1 EP 0008877B1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
ester
composition
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP79301557A
Other languages
German (de)
English (en)
Other versions
EP0008877A1 (fr
Inventor
Irene Stirling
Brian Peter Clarke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Publication of EP0008877A1 publication Critical patent/EP0008877A1/fr
Application granted granted Critical
Publication of EP0008877B1 publication Critical patent/EP0008877B1/fr
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention provides the compounds of the formula (I): and esters thereof wherein R 1 is an alkyl group of up to 4 carbon atoms or a phenyl group and R 2 is a hydrogen atom or R 2 together with R, represents the residue of a fused benzene ring.
  • the compounds of this invention are preferably the parent acid of the formula (I) which generally exists as the zwitterion of the formula (II):
  • R 1 and R 2 in the compounds of the formulae (I) and (II) are joined to form the residue of a fused benzene ring.
  • R 1 is a phenyl group and R 2 is a hydrogen atom.
  • esters of the compounds of the formula (II) also form part of this invention, for example as the free base or as the acid addition salt, since such compounds may also be used to enhance the effectiveness of penicillins or cephalosporins.
  • esters of the compounds of the formula (I) include those of the formula (III) and (IV): wherein R 1 and R 2 are as defined in relation to formula (II) wherein A 1 is an alkyl group of 3-6 carbon atoms optionally substituted by an alkoxyl or wherein R, is as defined in relation to formula (II) or is a substituted phenyl group as present in a compound of the formula (III)-(VII) wherein A 1 is an alkyl group of 1-6 carbon atoms optionally substituted by an alkoxyl or acyloxyl group of 1-7 carbon atoms; A 2 is an alkenyl or alkynyl group of up to 5 carbon atoms or is a phenyl group optionally substituted by a fluorine, chlorine, bromine, nitro or alkyl or alkoxyl of up to 4 carbon atoms; and A3 is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl
  • Suitable esters of the compounds of the formula (II) include the methyl, ethyl, n-propyl, n-butyl, allyl, CH 2 ⁇ C ⁇ CH, methoxymethyl, acetoxymethyl, propionoxymethyl, pivaloyloxymethyl, ethoxycarbonyloxymethyl, methoxycarbonyloxyethyl, ethoxycarbonyloxyethyl, dimethoxyphthalidyl, benzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, chlorobenzyl or the like ester.
  • Certain favoured groups A include the methyl, methoxymethyl, acetoxymethyl, acetoxyethyl, phthalidyl, ethoxycarbonyloxymethyl, a-ethoxycarbonyloxyethyl and the like groups.
  • Certain favoured groups A 2 include the phenyl and 4-methoxyphenyl groups.
  • a particularly favoured moiety A3 is the hydrogen atom.
  • a 5 is a hydrogen atom or a methyl group and A a is an alkyl group of up to 4 carbon atoms or a phenyl or benzyl group either of which may be substituted by one or two alkyl or alkoxyl groups of up to 3 carbon atoms or by a fluorine, chlorine or bromine atom or a nitro group; or A 5 is joined to A 6 to form the residue of an unsubstituted saturated 5- or 6-membered heteroalicyclic ring or an ortho-phenylene group which may be substituted by one or two alkyl or alkoxyl groups of up to 3 carbon atoms or by a fluorine, chlorine or bromine atom or nitro group.
  • An apt acylic value for the sub-group of the formula (c) is -CH 2- OA a .
  • An apt acylic value for the sub-group of the formula (d) is -CHz-CO-A6.
  • An apt acylic value for the sub-group of the formula (e) is ⁇ CH 2 ⁇ CO 2 A 6 .
  • a further apt acylic value for the sub-group of the formula (e) is ⁇ CH(CH 3 ) ⁇ CO 2 A 6 .
  • Favoured values for A 6 in the preceding acylic moieties include the methyl, ethyl, propyl, butyl, phenyl and benzyl groups.
  • Apt cyclic values for the sub-group of the formula (c) include the tetrahydropyranyl and tetrahydrofuranyl groups.
  • Esters of the compounds of the formula (I) may be presented in the form of their acid addition salts if desired.
  • the acid used to form the salt will most suitably be pharmaceutically acceptable, but non-pharmaceutically acceptable acid addition salts are also envisaged, for example as intermediates in the preparation of the pharmaceutically acceptable salts by ion exchange.
  • Suitable pharmaceutically acceptable acid addition salts include those of inorganic and organic acids, such as hydrochloric, phosphoric, sulphuric, methanesulphonic, toluenesulphonic, citric, malic, acetic, lactic, tartaric, propionic, succinic or the like acid.
  • the acid addition salt is provided as a solid and preferably as a crystalline solid.
  • the present invention provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier.
  • compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of the infection in mammals including humans.
  • compositions of this invention include tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable powders and sterile forms suitable for injection or infusion.
  • Such compositions may contain conventional pharmaceutically acceptable materials such as diluents, binders, colours, flavours, preservatives, disintegrant and the like in accordance with conventional pharmaceutical practice in the manner well understood by those skilled in the art of formulating antibiotics.
  • compositions of a compound of the invention are particularly suitable as high blood levels of the compound can occur after administration by injection or infusion.
  • one preferred composition aspect of this invention comprises a compound of the invention in sterile form and most suitably in sterile crystalline form.
  • the zwitterionic compounds of this invention are particularly suitable for use in such compositions.
  • the injectable solution of the compound of this invention may be made up in a sterile pyrogen- free liquid such as water, aqueous ethanol.
  • An alternative approach to administering the compounds of this invention and especially those zwitterionic compounds of the formula (11) is to utilise an injectable suspension.
  • Such suspensions may be made up in sterile water; sterile saline or the like and may also contain suspending agents such as polyvinylpyrrolidone, lecithin (for example in the manner described for amoxycillin trihydrate in Belgian Patent No. 839109).
  • suspending agents such as polyvinylpyrrolidone, lecithin (for example in the manner described for amoxycillin trihydrate in Belgian Patent No. 839109).
  • such compositions may be prepared in an acceptable oily suspending agent such as acharis oil or its equivalent.
  • the use of suspensions can give rise to advantageously prolonged blood levels of the medicament.
  • Belgian Patent No. 839109 may be consulted for suitable methods and materials for producing injectable aqueous suspensions.
  • the zwitterionic compound of this invention should be in the form of fine particles as described in said
  • Unit dose compositions comprising a compound of this invention adapted for oral administration form a further suitable composition aspect of this invention.
  • orally administrable forms are generally less favoured than injectable forms owing to the relatively poor absorption of the compounds from the gastro-intestinal tract.
  • this orally administrable compositions are of use as a synergistically effective blood level can be expected at high doses and at lower doses such compositions may be used to treat infections localised in the gastro-intestinal tract.
  • Unit dose compositions comprising a compound of this invention adapted for topical administration are also presented by this invention.
  • 'topical administration' also includes local administration to internal surfaces of mammary glands of cattle, for example during the treatment of mastitis by intra-mammary administration.
  • the compound of the formula may be present in the composition as sole therapeutic agent or it may be present together with other therapeutic agents such as a penicillin or cephalosporin. Considerable advantages accrue from the inclusion of a penicillin or cephalosporin since the resulting composition shows enhanced effectiveness (synergy).
  • Suitable penicillins for inclusion in the compositions of this invention include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, azidocillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin, cyclacillin, pirbenicillin, azlocillin, mezlocillin, celbenicillin, and other known penicillins including prodrugs therefore such as their in-vivo hydrolysable esters such as the acetoxymethyl, pivaloyloxymethyl, a-ethoxycarbonyloxyethyl or phthalidyl esters of ampicillin, benzylpenicillin or amoxycillin, and aldehyde or ketone adducts of penicillins containing an 6-a-aminoacetamide side chain (such as hetacillin, metampicillin and analogous derivatives of amoxycillin) or a-esters of carbenicillin or ticarcillin such as their phenyl or ind
  • Suitable cephalosporins for inclusion in the compositions of this invention include 'cefatrizine, cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole nafate, cephapirin, cepradine, 4-hydroxycephalexin, cefaparole, cephaloglycin, and other known cephalosporins or prodrugs thereof.
  • Such compounds are frequently used in the form of a salt or hydrate.
  • the composition will be adapted for parenteral administration. As previously indicated such injectable or infusable compositions are preferred.
  • Such penicillins may be used as a pharmaceutically acceptable salt such as the sodium salt.
  • the ampicillin or amoxycillin may be used in the form of fine particles of the zwitterionic form (generally as ampicillin trihydrate or amoxycillin trihydrate) for use in an injectable suspension, for example, in the manner hereinbefore described for a compound of this invention.
  • the preferred penicillin for use in the synergistic composition is amoxycillin, for example as its sodium salt or trihydrate.
  • the ratio of a compound of the invention to the penicillin or cephalosporin agent may vary over a wide range of ratios, such as from 10:1 to 1:10 for example about 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5 or 1:6, (wt/wt based on pure free antibiotic equivalent).
  • Orally administrable compositions containing a compound of the invention will normally contain relatively more synergist than corresponding injectable compositions, for example the ratio in an oral composition may be from about 3:1 to about 1:1 whereas a corresponding injectable composition may contain a ratio of about 1:1 to about 1:3 (compound of the invention: penicillin or cephalosporin).
  • the total quantity of a compound of the invention in any unit dosage form will normally be between 25 and 1000 mg and will usually be between 50 and 500 mg, for example about 62.5, 100, 125, 150, 200 or 250 mg.
  • compositions of this invention may be used for the treatment of infections of inter alia, the respiratory tract, the urinary tract and soft tissues in humans and mastitis in cattle.
  • the penicillin or cephalosporin in the synergistic composition of this invention will normally be present at approximately the amount at which it is conveniently used which will usually be expected to be from 62.5 to 1000 mg per dose, more usually about 125, 250 or 500 mg per dose.
  • composition of this invention will contain from 150 to 1000 mg of amoxycillin as the trihydrate or sodium salt and from 25 to 500 mg of a compound of this invention.
  • composition will contain a compound of the formula (11).
  • composition of this invention will contain from 150 to 1000 mg of ampicillin or a pro-drug therefor and from 25 to 500 mg of a compound of this invention.
  • this form of composition will contain ampicillin trihydrate, ampicillin anhydrate, sodium ampicillin, hetacillin, pivampicillinhydrochloride, bacampicillin hydrochloride or talampicillin hydrochloride. Most suitably this form of the composition will contain a compound of the formula (II).
  • the preceding compositions will contain from 200 to 700 mg of the penicillin component. Most suitably the preceding composition will comprise from 50 to 250 mg of a compound of the formula (II) preferably in crystalline form.
  • compositions may be adapted for oral or parenteral use except when containing an in-vivo hydrolysable ester of ampicillin or amoxycillin in which case the compositions will not be adapted for parenteral administration.
  • composition of this invention will contain from 200 to 2000 mg of carbenicillin, ticarcillin and from 50 to 500 mg of a compound of the invention.
  • this form of composition will contain di-sodium carbenicillin.
  • this form of the composition will contain di-sodium ticarcillin.
  • this form of the composition will contain from 75 to 250 mg of a compound of the formula (II) preferably in crystalline form.
  • Such compositions containing di-salts of carbenicillin and ticarcillin will be adapted for parenteral administration.
  • the infection treated will be due to a strain of Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, or the like.
  • Other organisms which may be treated by an antibacterially effective amount of a compound of this invention are strains of Klebsiella and Escherichia. These other organisms named are more readily treated by using a synergistically effective amount of the compound of the invention and a penicillin or cephalosporin.
  • the administration of the two components may take place separately but in general we prefer to use a composition containing both the synergist and the penicillin or cephalosporin.
  • the indications for treatment include respiratory tract and urinary tract infections in humans and mastitis in cattle.
  • the present invention also provides a process for the preparation of a compound of the formula (II) as hereinbefore defined or an ester thereof which process comprises the reaction of an ester of a 9-O-acyl derivative of clavulanic acid with an amine of the formula (V): wherein R 1 and R 2 are as defined in relation to formula (I); and thereafter if desired converting the thus formed ester of the compound of the formula (I) into the compound of the formula (I):
  • Suitable 9-0-acyl derivatives of clavulanic acid include those described in British Patent Specification Number 1604822, and West German Offenlegungsschrift No. P.2817085.6.
  • a particularly suitable 9-0-acyl derivative is the 9-0-dichloroacetyl derivative.
  • the displacement reaction may be carried out in a dry polar non-hydroxylic organic solvent such as dimethylformamide.
  • a depressed temperature is employed, for example 0-5°C.
  • the desired product may be obtained by dilution with ethyl acetate, washing to remove water soluble materials, drying the organic phase and evaporating under reduced pressure.
  • the initial crude product may then be purified chromatographically for example over silica eluting with ethyl acetate.
  • the ester of clavulanic employed is generally one cleavable by hydrogenation, for example the benzyl ester or a substituted benzyl ester such as a nitrobenzyl, chlorobenzyl, bromobenzyl or methoxybenzyl ester.
  • the preferred ester is the benzyl ester.
  • the desired compound of the formula (I) may be obtained from its hydrogenolysable ester by hydrogenation in the presence of a palladium catalyst, for example palladium on carbon.
  • a palladium catalyst for example palladium on carbon.
  • a one atmosphere pressure of hydrogen may be employed at ambient temperature.
  • the zwitterion may be obtained from the reaction mixture by filtering off and washing the solids and evaporating the filtrate.
  • the resulting compound is often somewhat crude but extraction of impurities into an organic solvent such as acetonitrile can result in the production of the zwitterion in crystalline form.
  • Example 2 has demonstrated good anti-bacterial activity in-vivo. When tested in mice suffering from an intraperitoneal infection of Staphylococcus aureus Smith, the following results were obtained with sub-cutaneous dosing 1 and 5 hours post infection: No overt drug induced toxicity was observed at the therapeutic dose.
  • the compound of Example 2 when present at 1 ⁇ g/ml reduced the in-vitro MIC of ampicillin against Klebsiella aerogenes E70 from 125 ⁇ g/ml to 3.1 ⁇ g/ml and against E. coli JT39 (R tem ) from 2000 ⁇ g/ml.
  • E. coli E96 R tem
  • the CD 50 of amoxycillin was reduced from > 1000 mg/kg to 22 mg/kg in the presence of 2 mg/kg of the compound of Example 2.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Claims (10)

1. Composé de formule (1):
Figure imgb0019
ou ester de ce composé ou sel d'addition avec un acide d'un tel ester, formule dans laquelle R1 est un groupe alcoyle ayant jusqu'à 4 atomes de carbone ou un groupe phényle et R2 est un atome d'hydrogène, ou bien R2 représente avec R1 le reste d'un cycle benzène fusionné.
2. Composé suivant la revendication 1, caractérisé en ce qu'un ester ou sel d'addition avec un acide quelconque de ce composé est pharmaceutiquement acceptable.
3. Composé suivant la revendication 1, constitué par l'acide 9-N-(1,2,3,4-tétrahydroisoquinolyl)désoxyclavulanique.
4. Composé suivant la revendication 1, constitué par l'acide 9-N-(4-phényl-1,2,3,6-tétra- hydropyridyl)désoxyclavulanique.
5. Ester benzylique d'un composé de formule (I) suivant la revendication 3 ou 4.
6. Composition pharmaceutique renfermant un composé suivant l'une quelconque des revendications 2 à 5 et un véhicule ou excipient pharmaceutiquement acceptable pour celui-ci.
7. Composition suivant la revendication 5, renfermant également une pénicilline ou une céphalosporine.
8. Composition suivant la revendication 6, renfermant également le sel de sodium d'amoxicilline, cette composition étant adaptée en vue d'une administration par injection.
9. Procédé pour la préparation d'un composé suivant la revendication 1, ce procédé consistant à effectuer la réaction d'un ester d'un dérivé 9-0-acylé d'acide clavulanique avec une amine de formule (V):
Figure imgb0020
dans laquelle R1 et R2 sont tels que définis dans la revendication 1, puis si désiré à convertir l'ester ainsi formé du composé de formule (I) en composé de formule (I).
10. Composé suivant l'une quelconque des revendications 2 à 5, destiné à être utilisé comme inhibiteur de β-lactamase ou comme agent antibactérien.
EP79301557A 1978-09-09 1979-08-03 Dérivés d'acide clavulanique, un procédé pour leur préparation et leurs compositions Expired EP0008877B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB7836268 1978-09-09
GB3626878 1978-09-09

Publications (2)

Publication Number Publication Date
EP0008877A1 EP0008877A1 (fr) 1980-03-19
EP0008877B1 true EP0008877B1 (fr) 1983-10-26

Family

ID=10499574

Family Applications (1)

Application Number Title Priority Date Filing Date
EP79301557A Expired EP0008877B1 (fr) 1978-09-09 1979-08-03 Dérivés d'acide clavulanique, un procédé pour leur préparation et leurs compositions

Country Status (4)

Country Link
US (2) US4301168A (fr)
EP (1) EP0008877B1 (fr)
JP (1) JPS5538370A (fr)
DE (1) DE2966349D1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1582884A (en) * 1977-05-19 1981-01-14 Beecham Group Ltd Clavulanic acid derivatives their preparation and use
DK330880A (da) * 1979-08-03 1981-02-04 Beecham Group Ltd Fremgangsmaade til fremstilling af clavulansyrederivater
EP0028083B1 (fr) * 1979-10-26 1984-02-08 Beecham Group Plc Dérivés de l'acide clavulanique, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0053893B1 (fr) * 1980-12-09 1985-03-20 Beecham Group Plc Dérivés de l'acide clavulanique, leur préparation et leur application
NZ199200A (en) * 1980-12-23 1984-07-31 Beecham Group Ltd Clavulanic acid derivatives and pharmaceutical compositions
WO1998022110A1 (fr) * 1996-11-20 1998-05-28 Virginia Tech Intellectual Properties, Inc. Promedicaments pour l'inhibition selective de la monoamine oxydase-b

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU503489B2 (en) * 1975-10-13 1979-09-06 Beecham Group Limited Substituted aminodeoxy clavulanic acid
GB1594934A (en) * 1976-10-25 1981-08-05 Glaxo Lab Ltd Clavulanic acid derivatives
ZA785711B (en) * 1977-10-10 1979-09-26 Glaxo Group Ltd B-lactam compounds,process for their preparation,pharmaceutical compositions containing them and intermediates of use in their preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Medicinal Chemistry B, 1978, Chapter 16, "Structure-Activity Relationship of "Non-Classical" Beta-Lactam Antibiotics", pages 149-156 *

Also Published As

Publication number Publication date
US4301168A (en) 1981-11-17
EP0008877A1 (fr) 1980-03-19
JPS5538370A (en) 1980-03-17
US4444754A (en) 1984-04-24
DE2966349D1 (en) 1983-12-01

Similar Documents

Publication Publication Date Title
US4382084A (en) Antibiotics
EP0008877B1 (fr) Dérivés d'acide clavulanique, un procédé pour leur préparation et leurs compositions
EP0055062B1 (fr) Composés contenant des bêta-lactames
EP0025271B1 (fr) Dérivés de l'acide clavulanique, leur préparation et compositions pharmaceutiques les contenant
EP0008884B1 (fr) Dérivés de l'acide clavulanique, un procédé pour leur préparation et leurs compositions
EP0007717B1 (fr) Dérivés de l'acide clavulanique, un procédé pour leur préparation, leur utilisation et compositions pharmaceutiques les contenant
EP0002319B1 (fr) Dérivés de l'acide clavulanique, procédé pour leur préparation et compositions les contenant
US4426389A (en) Derivatives of clavulanic acid, a process for their preparation and their use
US4388300A (en) Clavulanic acid derivatives, a process for their preparation and their use in pharmaceutical compositions
EP0028083B1 (fr) Dérivés de l'acide clavulanique, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4303665A (en) Methylaminodeoxy-clavulanic acid derivatives, their production and use
EP0112685B1 (fr) Composés contenant des bêta-lactames
EP0021836B1 (fr) Dérivés de l'acide clavulanique, procédé pour leur préparation et compositions pharmaceutiques les contenant
US4409207A (en) Derivatives of clavulanic acid, a process for their preparation and their use
EP0027323B1 (fr) Dérivés de l'acide clavulanique, procédés pour leur préparation et compositions pharmaceutiques les contenant
CA1148085A (fr) Derives de l'acide clavulanique, procede de preparation et utilisation
US4539202A (en) Derivatives of clavulanic acid, a process for their preparation and their use
EP0080285A1 (fr) Composés thérapeutiques contenant des bêta-lactames
EP0062407A1 (fr) Composés thérapeutiques à cycle bête-lactame
WO1984002134A1 (fr) COMPOSES CONTENANT DES beta-LACTAMES
EP0080284A1 (fr) Dérivés de l'acide clavulanique, procédés pour leur préparation et leur application

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): CH DE FR GB IT NL

17P Request for examination filed
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BEECHAM GROUP PLC

ITF It: translation for a ep patent filed
RBV Designated contracting states (corrected)

Designated state(s): CH DE FR GB IT NL

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): CH DE FR GB IT NL

ET Fr: translation filed
REF Corresponds to:

Ref document number: 2966349

Country of ref document: DE

Date of ref document: 19831201

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19840831

26N No opposition filed
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19850301

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19850430

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19850501

GBPC Gb: european patent ceased through non-payment of renewal fee
REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19881118